Elucidating circuit disruptions in Alzheimer's disease

阐明阿尔茨海默病的电路中断

• 批准号: 10055533
• 负责人: Ksenia V. Kastanenka
• 金额: $ 57.44万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10055533
• 关键词: Adopted; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease patient; Amyloidosis; Astrocytes; Autopsy; Brain; Calcium; Cells; Chronic; Clinical Trials; Cognitive; Coupling; Data; Dementia; Deposition; Development; Disease; Disease Progression; Electrodes; Electrophysiology (science); Elements; Etiology; Exhibits; Failure; Fourier Transform; Functional disorder; Glutamate-Ammonia Ligase; Glutamates; Glutaminase; Glutamine; Goals; Health; High Pressure Liquid Chromatography; Homeostasis; Hyperactive behavior; Image; Impaired cognition; Individual; Lead; Memory impairment; Metabolic; Molecular; Mus; Neurodegenerative Disorders; Neuroglia; Neurons; Neurosciences; Pattern; Play; Population; Process; Proteins; Regulation; Reporting; Rodent; Rodent Diseases; Role; Senile Plaques; Sleep; Testing; Therapeutic; Transgenic Mice; Work; behavior measurement; brain tissue; gamma-Aminobutyric Acid; in vivo calcium imaging; interest; macroglia; memory consolidation; molecular marker; mouse model; multiphoton microscopy; network dysfunction; neuronal circuitry; neuropathology; neurotransmission; non rapid eye movement; novel; novel therapeutic intervention; optogenetics; restoration; therapeutic development; tool; voltage sensitive dye

Summary Alzheimer’s disease (AD) is the major cause of dementia currently without an effective cure. A number of clinical trial failures has been reported due to a lack of complete understanding of Alzheimer’s disease etiology. Neuronal activity disruptions have been described as contributing factors to the disease etiology and its progression. Anomalies in slow wave activity, specifically slow oscillations (oscillations <1Hz) important for consolidation of memories during NREM sleep, have been reported in Alzheimer’s patients and might have contributed to their dementia. The cellular mechanisms of such disruptions however are unclear. Contributions of neuronal hyperactivity have been suggested. It is unknown whether macroglia contribute to hyperactivity and slow wave aberrations. Thus, there is an urgent need to understand the impact of macroglia on neuronal activity disruptions, such as slow waves, to better understand AD etiology and to alleviate its dementia burden. We will use transgenic mouse models of Alzheimer’s disease to systematically assess whether macroglia contributes to neuronal activity disruptions using calcium imaging with multiphoton microscopy. We will also investigate whether macroglia play a causal role in disruption of slow wave activity using optogenetics. We hypothesize that macroglia play a role greater than that of a homeostatic regulator of neuronal activity. We propose to employ optogenetics to control neuronal circuits aimed to restore neuronal activity and slow Alzheimer’s disease progression. Thus, our findings will determine the cellular and molecular relationships between neuronal activity and AD, with the targeting of macroglia as a novel therapeutic approach.

概括 阿尔茨海默氏病（AD）是目前尚无有效治疗方法的痴呆症的主要原因。 由于缺乏对阿尔茨海默氏病病因的完全了解，已有临床试验失败的报告。 神经元活动中断已被描述为导致该疾病的病因及其发病机制的因素。 慢波进展活动的异常，特别是慢振荡（振荡<1Hz）对于 据报道，阿尔茨海默病患者在 NREM 睡眠期间会巩固记忆，这可能与 然而，这种破坏的细胞机制尚不清楚。 目前尚不清楚大胶质细胞是否会导致神经过度活跃。 因此，迫切需要了解大胶质细胞对神经元的影响。 活动中断，例如慢波，以更好地了解 AD 病因并减轻其痴呆症负担。 我们将使用阿尔茨海默病的转基因小鼠模型来系统地评估大胶质细胞是否 我们还将使用多光子显微镜的钙成像来破坏神经元活动。 使用光遗传学研究大胶质细胞是否在慢波活动破坏中发挥因果作用。 大胶质细胞的作用大于神经元活动的稳态调节器。 提议采​​用光遗传学来控制神经回路，旨在恢复神经活动并减缓 因此，我们的研究结果将确定细胞和分子关系。 神经元活动与 AD 之间的关系，以大胶质细胞为靶点作为一种新的治疗方法。